Amphiuma red cells incubated in anisotonic media regulate their volume by using specific transport mechanisms for Na and K. The Na uptake mechanism of the response to hypertonicity is blocked by amiloride, but is stimulated following pretreatment with amiloride. Two-thirds of this pretreatment effect can be attributed to amiloride blockage of volume changes; about one-third appears to be due to some other action of the drug.